Purpose :
Of the millions affected by Age-related macular degeneration (AMD), the vast majority have the dry “atrophic” form of the disease, a type of AMD for which options to prevent and treat are most limited. Age and race are non-modifiable risk factors; however, oxidative stress, inflammation, altered cholesterol and dysregulated energy metabolism, factors that can potentially be modified, also play major causative roles. Nicotinamide adenine dinucleotide (NAD+) plays an essential role in many processes (i.e., cellular metabolism, ATP production and DNA repair) and is a required factor for the anti-aging protein deacetylase, SIRT1. Decreased NAD+ and SIRT1 are common in aging and are linked strongly to the development of age-related pathologies such as Alzheimer’s, various cancers, and potentially AMD. Our prior work has shown monomethylfumarate (MMF) to impact oxidative stress, inflammation and cholesterol metabolism in retinal pigment epithelial (RPE) cells, a cell type whose dysfunction is integral to AMD development. In the present study, we evaluated the effect of the compound on cellular energy metabolism and its potential therapeutic utility in the context of pathology relevant to AMD.

Methods :
Human retinal pigment epithelial (ARPE-19) cells were cultured in the presence of FK866 (0.01-10μM), a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biogenesis, in the presence or MMF (100-500μM). The impact of the treatments on markers of cell viability, senescence, oxidative stress and inflammation as well as SIRT1 expression and activity was evaluated using RT-qPCR, Western blotting and commercial activity assay kits.

Results :
FK866 treatment led to the time and dose-dependent depletion of NAD+, a factor associated with reduced SIRT1 and the increased expression of markers of cellular senescence, inflammation and oxidative stress. Co-culture of cells with MMF reversed these factors in a time- and dose-dependent manner.

Conclusions :
Therapies to boost NAD+/SIRT1 and limit oxidative stress, inflammation and cholesterol retention in retina may be of value in AMD. Our work shows MMF to be a strong potential candidate.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.